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Shikimic acid

February 15, 2024

Shikimic acid, more commonly known as its anionic form shikimate, is a cyclohexene, a cyclitol and a cyclohexanecarboxylic acid. It is an important biochemical metabolite in plants and microorganisms. Its name comes from the Japanese flower shikimi (シキミ, the Japanese star anise, Illicium anisatum), from which it was first isolated in 1885 by Johan Fredrik Eykman.[1] The elucidation of its structure was made nearly 50 years later.[2]

Shikimic acid
Chemical structure of shikimic acid
3D model of shikimic acid
Names
Preferred IUPAC name
(3R,4S,5R)-3,4,5-Trihydroxycyclohex-1-ene-1-carboxylic acid
Identifiers
  • 138-59-0 Y
3D model (JSmol)
  • Interactive image
ChEBI
  • CHEBI:16119 Y
ChEMBL
  • ChEMBL290345 Y
ChemSpider
  • 8412 Y
ECHA InfoCard 100.004.850
EC Number
  • 205-334-2
KEGG
  • C00493 N
  • 8742
UNII
  • 29MS2WI2NU N
  • DTXSID4032039
  • InChI=1S/C7H10O5/c8-4-1-3(7(11)12)2-5(9)6(4)10/h1,4-6,8-10H,2H2,(H,11,12)/t4-,5-,6-/m1/s1 Y
    Key: JXOHGGNKMLTUBP-HSUXUTPPSA-N Y
  • InChI=1/C7H10O5/c8-4-1-3(7(11)12)2-5(9)6(4)10/h1,4-6,8-10H,2H2,(H,11,12)/t4-,5-,6-/m1/s1/f/h11H
  • InChI=1/C7H10O5/c8-4-1-3(7(11)12)2-5(9)6(4)10/h1,4-6,8-10H,2H2,(H,11,12)/t4-,5-,6-/m1/s1
    Key: JXOHGGNKMLTUBP-HSUXUTPPBZ
  • C1[C@H]([C@@H]([C@@H](C=C1C(=O)O)O)O)O
Properties
C7H10O5
Molar mass 174.15 g/mol
Melting point 185 to 187 °C (365 to 369 °F; 458 to 460 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YN ?)

Biosynthesis edit

Phosphoenolpyruvate and erythrose-4-phosphate condense to form 3-deoxy-D-arabinoheptulosonate-7-phosphate (DAHP), in a reaction catalyzed by the enzyme DAHP synthase. DAHP is then transformed to 3-dehydroquinate (DHQ), in a reaction catalyzed by DHQ synthase. Although this reaction requires nicotinamide adenine dinucleotide (NAD) as a cofactor, the enzymic mechanism regenerates it, resulting in the net use of no NAD.

 
Biosynthesis of 3-dehydroquinate from phosphoenolpyruvate and erythrose-4-phosphate

DHQ is dehydrated to 3-dehydroshikimic acid by the enzyme 3-dehydroquinate dehydratase, which is reduced to shikimic acid by the enzyme shikimate dehydrogenase, which uses nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor.

 
Biosynthesis of shikimic acid from 3-dehydroquinate

Shikimate pathway edit

Main article: Shikimate pathway

Biosynthesis of the aromatic amino acids edit

The shikimate pathway is a seven-step metabolic route used by bacteria, fungi, algae, parasites, and plants for the biosynthesis of aromatic amino acids (phenylalanine, tyrosine, and tryptophan). This pathway is not found in animals; therefore, phenylalanine and tryptophan represent essential amino acids that must be obtained from the animal's diet (animals can synthesise tyrosine from phenylalanine, and therefore is not an essential amino acid except for individuals unable to hydroxylate phenylalanine to tyrosine).

The seven enzymes involved in the shikimate pathway are DAHP synthase, 3-dehydroquinate synthase, 3-dehydroquinate dehydratase, shikimate dehydrogenase, shikimate kinase, EPSP synthase, and chorismate synthase. The pathway starts with two substrates, phosphoenol pyruvate and erythrose-4-phosphate and ends with chorismate, a substrate for the three aromatic amino acids. The fifth enzyme involved is the shikimate kinase, an enzyme that catalyzes the ATP-dependent phosphorylation of shikimate to form shikimate 3-phosphate (shown in the figure below).[3] Shikimate 3-phosphate is then coupled with phosphoenol pyruvate to give 5-enolpyruvylshikimate-3-phosphate via the enzyme 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase.

 

Then 5-enolpyruvylshikimate-3-phosphate is transformed into chorismate by a chorismate synthase.

 

Prephenic acid is then synthesized by a Claisen rearrangement of chorismate by chorismate mutase.[4][5]

 

Prephenate is oxidatively decarboxylated with retention of the hydroxyl group to give p-hydroxyphenylpyruvate, which is transaminated using glutamate as the nitrogen source to give tyrosine and α-ketoglutarate.

 

Starting point in the biosynthesis of some phenolics edit

Phenylalanine and tyrosine are the precursors used in the phenylpropanoids biosynthesis. The phenylpropanoids are then used to produce the flavonoids, coumarins, tannins and lignin. The first enzyme involved is phenylalanine ammonia-lyase (PAL) that converts L-phenylalanine to trans-cinnamic acid and ammonia.

Gallic acid biosynthesis edit

Gallic acid is formed from 3-dehydroshikimate by the action of the enzyme shikimate dehydrogenase to produce 3,5-didehydroshikimate. This latter compound spontaneously rearranges to gallic acid.[6]

Other compounds edit

Shikimic acid is a precursor for:

Mycosporine-like amino acids edit

Mycosporine-like amino acids are small secondary metabolites produced by organisms that live in environments with high volumes of sunlight, usually marine environments.

Uses edit

In the pharmaceutical industry, shikimic acid from the Chinese star anise (Illicium verum) is used as a base material for production of oseltamivir (Tamiflu). Although shikimic acid is present in most autotrophic organisms, it is a biosynthetic intermediate and in general found in very low concentrations. The low isolation yield of shikimic acid from the Chinese star anise is blamed for the 2005 shortage of oseltamivir. Shikimic acid can also be extracted from the seeds of the sweetgum (Liquidambar styraciflua) fruit,[2] which is abundant in North America, in yields of around 1.5%. For example, 4 kg (8.8 lb) of sweetgum seeds is needed for fourteen packages of Tamiflu. By comparison, star anise has been reported to yield 3% to 7% shikimic acid. Biosynthetic pathways in E. coli have recently been enhanced to allow the organism to accumulate enough material to be used commercially.[7][8][9] A 2010 study released by the University of Maine showed that shikimic acid can also be readily harvested from the needles of several species of pine tree.[10]

Protecting groups are more commonly used in small-scale laboratory work and initial development than in industrial production processes because their use adds additional steps and material costs to the process. However, the availability of a cheap chiral building block can overcome these additional costs, for example, shikimic acid for oseltamivir.

Aminoshikimic acid is also an alternative to shikimic acid as a starting material for the synthesis of oseltamivir.

Target for drugs edit

Shikimate can be used to synthesise (6S)-6-fluoroshikimic acid,[11] an antibiotic which inhibits the aromatic biosynthetic pathway.[12] More specifically, glyphosate inhibits the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS). "Roundup Ready" genetically modified crops overcome that inhibition.[13]

Occurrence edit

It occurs in tree fern fronds, a specialty called fiddlehead (furled fronds of a young tree fern in the order Cyatheales, harvested for use as a vegetable). These fronds are edible, but can be roasted to remove shikimic acid.[14]

Shikimic acid is also the glycoside part of some hydrolysable tannins. The acid is highly soluble in water and insoluble in nonpolar solvents, and this is why shikimic acid is active only against Gram-positive bacteria, due to outer cell membrane impermeability of Gram-negatives.[15]

See also edit

References edit

  1. ^ Eykman, J. F. (1881). "The botanical relations of Illicium religiosum Sieb., Illicium anisatum Lour". American Journal of Pharmacy. 53 (8).
  2. ^ a b Enrich, Liza B.; Scheuermann, Margaret L.; Mohadjer, Ashley; Matthias, Kathryn R.; Eller, Chrystal F.; Newman, M. Scott; Fujinaka, Michael; Poon, Thomas (April 2008). "Liquidambar styraciflua: a renewable source of shikimic acid". Tetrahedron Letters. 49 (16): 2503–2505. doi:10.1016/j.tetlet.2008.02.140.
  3. ^ Herrmann, K. M.; Weaver, L. M. (1999). "The Shikimate Pathway". Annual Review of Plant Physiology and Plant Molecular Biology. 50: 473–503. doi:10.1146/annurev.arplant.50.1.473. PMID 15012217.
  4. ^ Goerisch, H. (1978). "On the mechanism of the chorismate mutase reaction". Biochemistry. 17 (18): 3700–3705. doi:10.1021/bi00611a004. PMID 100134.
  5. ^ Kast, P.; Tewari, Y. B.; Wiest, O.; Hilvert, D.; Houk, K. N.; Goldberg, Robert N. (1997). "Thermodynamics of the Conversion of Chorismate to Prephenate: Experimental Results and Theoretical Predictions". Journal of Physical Chemistry B. 101 (50): 10976–10982. doi:10.1021/jp972501l.
  6. ^ "Gallic acid pathway". metacyc.org.
  7. ^ Bradley, D. (December 2005). "Star role for bacteria in controlling flu pandemic?". Nature Reviews Drug Discovery. 4 (12): 945–946. doi:10.1038/nrd1917. PMID 16370070. S2CID 30035056.
  8. ^ Krämer, M.; Bongaerts, J.; Bovenberg, R.; Kremer, S.; Müller, U.; Orf, S.; Wubbolts, M.; Raeven, L. (2003). "Metabolic engineering for microbial production of shikimic acid". Metabolic Engineering. 5 (4): 277–283. doi:10.1016/j.ymben.2003.09.001. PMID 14642355.
  9. ^ Johansson, L.; Lindskog, A.; Silfversparre, G.; Cimander, C.; Nielsen, K. F.; Liden, G. (2005). "Shikimic acid production by a modified strain of E. coli (W3110.shik1) under phosphate-limited and carbon-limited conditions". Biotechnology and Bioengineering. 92 (5): 541–552. doi:10.1002/bit.20546. PMID 16240440. S2CID 19659961.
  10. ^ "Maine pine needles yield valuable Tamiflu material". Boston.com. 7 November 2010.
  11. ^ Song, Chuanjun; Jiang, Shende; Singh, Gurdial (4 August 2011). "Facile Syntheses of (6S)-6-Fluoroshikimic Acid and (6R)-6-Hydroxyshikimic Acid". Chemical Research in Chinese Universities. 18 (2): 146–152.
  12. ^ Davies, G M; Barrett-Bee, K J; Jude, D A; Lehan, M; Nichols, W W; Pinder, P E; Thain, J L; Watkins, W J; Wilson, R G (February 1994). "(6S)-6-fluoroshikimic acid, an antibacterial agent acting on the aromatic biosynthetic pathway". Antimicrobial Agents and Chemotherapy. 38 (2): 403–406. doi:10.1128/AAC.38.2.403. PMC 284469. PMID 8192477.
  13. ^ Funke, T.; Han, H.; Healy-Fried, M. L.; Fischer, M.; Schonbrunn, E. (29 August 2006). "Molecular basis for the herbicide resistance of Roundup Ready crops". Proceedings of the National Academy of Sciences. 103 (35): 13010–13015. Bibcode:2006PNAS..10313010F. doi:10.1073/pnas.0603638103. PMC 1559744. PMID 16916934.
  14. ^ Evans, I. A.; Osman, M. A. (July 1974). "Carcinogenicity of bracken and shikimic acid". Nature. 250 (5464): 348–349. Bibcode:1974Natur.250..348E. doi:10.1038/250348a0. PMID 4211848. S2CID 4175635.
  15. ^ Chung, Hai-Jung (30 September 2009). "Evaluation of the Biological Activity of Extracts from Star-Anise (Illicium verum)". Preventive Nutrition and Food Science. 14 (3): 195–200. doi:10.3746/jfn.2009.14.3.195.

Books edit

February 15, 2024
shikimic, acid, more, commonly, known, anionic, form, shikimate, cyclohexene, cyclitol, cyclohexanecarboxylic, acid, important, biochemical, metabolite, plants, microorganisms, name, comes, from, japanese, flower, shikimi, シキミ, japanese, star, anise, illicium,. Shikimic acid more commonly known as its anionic form shikimate is a cyclohexene a cyclitol and a cyclohexanecarboxylic acid It is an important biochemical metabolite in plants and microorganisms Its name comes from the Japanese flower shikimi シキミ the Japanese star anise Illicium anisatum from which it was first isolated in 1885 by Johan Fredrik Eykman 1 The elucidation of its structure was made nearly 50 years later 2 Shikimic acid Chemical structure of shikimic acid 3D model of shikimic acidNamesPreferred IUPAC name 3R 4S 5R 3 4 5 Trihydroxycyclohex 1 ene 1 carboxylic acidIdentifiersCAS Number 138 59 0 Y3D model JSmol Interactive imageChEBI CHEBI 16119 YChEMBL ChEMBL290345 YChemSpider 8412 YECHA InfoCard 100 004 850EC Number 205 334 2KEGG C00493 NPubChem CID 8742UNII 29MS2WI2NU NCompTox Dashboard EPA DTXSID4032039InChI InChI 1S C7H10O5 c8 4 1 3 7 11 12 2 5 9 6 4 10 h1 4 6 8 10H 2H2 H 11 12 t4 5 6 m1 s1 YKey JXOHGGNKMLTUBP HSUXUTPPSA N YInChI 1 C7H10O5 c8 4 1 3 7 11 12 2 5 9 6 4 10 h1 4 6 8 10H 2H2 H 11 12 t4 5 6 m1 s1 f h11HInChI 1 C7H10O5 c8 4 1 3 7 11 12 2 5 9 6 4 10 h1 4 6 8 10H 2H2 H 11 12 t4 5 6 m1 s1Key JXOHGGNKMLTUBP HSUXUTPPBZSMILES C1 C H C H C H C C1C O O O O OPropertiesChemical formula C 7H 10O 5Molar mass 174 15 g molMelting point 185 to 187 C 365 to 369 F 458 to 460 K Except where otherwise noted data are given for materials in their standard state at 25 C 77 F 100 kPa N verify what is Y N Infobox references Contents 1 Biosynthesis 2 Shikimate pathway 2 1 Biosynthesis of the aromatic amino acids 2 2 Starting point in the biosynthesis of some phenolics 2 2 1 Gallic acid biosynthesis 2 3 Other compounds 2 3 1 Mycosporine like amino acids 3 Uses 4 Target for drugs 5 Occurrence 6 See also 7 References 7 1 BooksBiosynthesis editPhosphoenolpyruvate and erythrose 4 phosphate condense to form 3 deoxy D arabinoheptulosonate 7 phosphate DAHP in a reaction catalyzed by the enzyme DAHP synthase DAHP is then transformed to 3 dehydroquinate DHQ in a reaction catalyzed by DHQ synthase Although this reaction requires nicotinamide adenine dinucleotide NAD as a cofactor the enzymic mechanism regenerates it resulting in the net use of no NAD nbsp Biosynthesis of 3 dehydroquinate from phosphoenolpyruvate and erythrose 4 phosphateDHQ is dehydrated to 3 dehydroshikimic acid by the enzyme 3 dehydroquinate dehydratase which is reduced to shikimic acid by the enzyme shikimate dehydrogenase which uses nicotinamide adenine dinucleotide phosphate NADPH as a cofactor nbsp Biosynthesis of shikimic acid from 3 dehydroquinateShikimate pathway editMain article Shikimate pathway Biosynthesis of the aromatic amino acids edit The shikimate pathway is a seven step metabolic route used by bacteria fungi algae parasites and plants for the biosynthesis of aromatic amino acids phenylalanine tyrosine and tryptophan This pathway is not found in animals therefore phenylalanine and tryptophan represent essential amino acids that must be obtained from the animal s diet animals can synthesise tyrosine from phenylalanine and therefore is not an essential amino acid except for individuals unable to hydroxylate phenylalanine to tyrosine The seven enzymes involved in the shikimate pathway are DAHP synthase 3 dehydroquinate synthase 3 dehydroquinate dehydratase shikimate dehydrogenase shikimate kinase EPSP synthase and chorismate synthase The pathway starts with two substrates phosphoenol pyruvate and erythrose 4 phosphate and ends with chorismate a substrate for the three aromatic amino acids The fifth enzyme involved is the shikimate kinase an enzyme that catalyzes the ATP dependent phosphorylation of shikimate to form shikimate 3 phosphate shown in the figure below 3 Shikimate 3 phosphate is then coupled with phosphoenol pyruvate to give 5 enolpyruvylshikimate 3 phosphate via the enzyme 5 enolpyruvylshikimate 3 phosphate EPSP synthase nbsp Then 5 enolpyruvylshikimate 3 phosphate is transformed into chorismate by a chorismate synthase nbsp Prephenic acid is then synthesized by a Claisen rearrangement of chorismate by chorismate mutase 4 5 nbsp Prephenate is oxidatively decarboxylated with retention of the hydroxyl group to give p hydroxyphenylpyruvate which is transaminated using glutamate as the nitrogen source to give tyrosine and a ketoglutarate nbsp Starting point in the biosynthesis of some phenolics edit Phenylalanine and tyrosine are the precursors used in the phenylpropanoids biosynthesis The phenylpropanoids are then used to produce the flavonoids coumarins tannins and lignin The first enzyme involved is phenylalanine ammonia lyase PAL that converts L phenylalanine to trans cinnamic acid and ammonia Gallic acid biosynthesis edit Gallic acid is formed from 3 dehydroshikimate by the action of the enzyme shikimate dehydrogenase to produce 3 5 didehydroshikimate This latter compound spontaneously rearranges to gallic acid 6 Other compounds edit Shikimic acid is a precursor for indole indole derivatives and aromatic amino acid tryptophan and tryptophan derivatives such as the psychedelic compound dimethyltryptamine many alkaloids and other aromatic metabolitesMycosporine like amino acids edit Mycosporine like amino acids are small secondary metabolites produced by organisms that live in environments with high volumes of sunlight usually marine environments Uses editIn the pharmaceutical industry shikimic acid from the Chinese star anise Illicium verum is used as a base material for production of oseltamivir Tamiflu Although shikimic acid is present in most autotrophic organisms it is a biosynthetic intermediate and in general found in very low concentrations The low isolation yield of shikimic acid from the Chinese star anise is blamed for the 2005 shortage of oseltamivir Shikimic acid can also be extracted from the seeds of the sweetgum Liquidambar styraciflua fruit 2 which is abundant in North America in yields of around 1 5 For example 4 kg 8 8 lb of sweetgum seeds is needed for fourteen packages of Tamiflu By comparison star anise has been reported to yield 3 to 7 shikimic acid Biosynthetic pathways in E coli have recently been enhanced to allow the organism to accumulate enough material to be used commercially 7 8 9 A 2010 study released by the University of Maine showed that shikimic acid can also be readily harvested from the needles of several species of pine tree 10 Protecting groups are more commonly used in small scale laboratory work and initial development than in industrial production processes because their use adds additional steps and material costs to the process However the availability of a cheap chiral building block can overcome these additional costs for example shikimic acid for oseltamivir Aminoshikimic acid is also an alternative to shikimic acid as a starting material for the synthesis of oseltamivir Target for drugs editShikimate can be used to synthesise 6S 6 fluoroshikimic acid 11 an antibiotic which inhibits the aromatic biosynthetic pathway 12 More specifically glyphosate inhibits the enzyme 5 enolpyruvylshikimate 3 phosphate synthase EPSPS Roundup Ready genetically modified crops overcome that inhibition 13 Occurrence editIt occurs in tree fern fronds a specialty called fiddlehead furled fronds of a young tree fern in the order Cyatheales harvested for use as a vegetable These fronds are edible but can be roasted to remove shikimic acid 14 Shikimic acid is also the glycoside part of some hydrolysable tannins The acid is highly soluble in water and insoluble in nonpolar solvents and this is why shikimic acid is active only against Gram positive bacteria due to outer cell membrane impermeability of Gram negatives 15 See also editAminoshikimate pathway a novel variation of the shikimate pathwayReferences edit Eykman J F 1881 The botanical relations of Illicium religiosum Sieb Illicium anisatum Lour American Journal of Pharmacy 53 8 a b Enrich Liza B Scheuermann Margaret L Mohadjer Ashley Matthias Kathryn R Eller Chrystal F Newman M Scott Fujinaka Michael Poon Thomas April 2008 Liquidambar styraciflua a renewable source of shikimic acid Tetrahedron Letters 49 16 2503 2505 doi 10 1016 j tetlet 2008 02 140 Herrmann K M Weaver L M 1999 The Shikimate Pathway Annual Review of Plant Physiology and Plant Molecular Biology 50 473 503 doi 10 1146 annurev arplant 50 1 473 PMID 15012217 Goerisch H 1978 On the mechanism of the chorismate mutase reaction Biochemistry 17 18 3700 3705 doi 10 1021 bi00611a004 PMID 100134 Kast P Tewari Y B Wiest O Hilvert D Houk K N Goldberg Robert N 1997 Thermodynamics of the Conversion of Chorismate to Prephenate Experimental Results and Theoretical Predictions Journal of Physical Chemistry B 101 50 10976 10982 doi 10 1021 jp972501l Gallic acid pathway metacyc org Bradley D December 2005 Star role for bacteria in controlling flu pandemic Nature Reviews Drug Discovery 4 12 945 946 doi 10 1038 nrd1917 PMID 16370070 S2CID 30035056 Kramer M Bongaerts J Bovenberg R Kremer S Muller U Orf S Wubbolts M Raeven L 2003 Metabolic engineering for microbial production of shikimic acid Metabolic Engineering 5 4 277 283 doi 10 1016 j ymben 2003 09 001 PMID 14642355 Johansson L Lindskog A Silfversparre G Cimander C Nielsen K F Liden G 2005 Shikimic acid production by a modified strain of E coli W3110 shik1 under phosphate limited and carbon limited conditions Biotechnology and Bioengineering 92 5 541 552 doi 10 1002 bit 20546 PMID 16240440 S2CID 19659961 Maine pine needles yield valuable Tamiflu material Boston com 7 November 2010 Song Chuanjun Jiang Shende Singh Gurdial 4 August 2011 Facile Syntheses of 6S 6 Fluoroshikimic Acid and 6R 6 Hydroxyshikimic Acid Chemical Research in Chinese Universities 18 2 146 152 Davies G M Barrett Bee K J Jude D A Lehan M Nichols W W Pinder P E Thain J L Watkins W J Wilson R G February 1994 6S 6 fluoroshikimic acid an antibacterial agent acting on the aromatic biosynthetic pathway Antimicrobial Agents and Chemotherapy 38 2 403 406 doi 10 1128 AAC 38 2 403 PMC 284469 PMID 8192477 Funke T Han H Healy Fried M L Fischer M Schonbrunn E 29 August 2006 Molecular basis for the herbicide resistance of Roundup Ready crops Proceedings of the National Academy of Sciences 103 35 13010 13015 Bibcode 2006PNAS 10313010F doi 10 1073 pnas 0603638103 PMC 1559744 PMID 16916934 Evans I A Osman M A July 1974 Carcinogenicity of bracken and shikimic acid Nature 250 5464 348 349 Bibcode 1974Natur 250 348E doi 10 1038 250348a0 PMID 4211848 S2CID 4175635 Chung Hai Jung 30 September 2009 Evaluation of the Biological Activity of Extracts from Star Anise Illicium verum Preventive Nutrition and Food Science 14 3 195 200 doi 10 3746 jfn 2009 14 3 195 Books edit Haslam E 1974 The Shikimate Pathway 1st ed Haslam Edwin 1993 Shikimic acid metabolism and metabolites Wiley ISBN 978 0 471 93999 3 Retrieved from https en wikipedia org w index php title Shikimic acid amp oldid 1141247877, wikipedia, wiki, book, books, library,

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